Only Michael Moore knew the combination to the safe in his bedroom closet. He had locked up his prescriptions for chronic pain and insomnia so his two young children could not get into them.

As it turned out, it was Moore, 49, who needed the protection.

On Nov. 3, 2012, Moore, a computer analyst from Milwaukee who had suffered a serious knee injury years earlier, died of an accidental overdose. When police opened the safe they found hundreds of two types of prescription pills: opioids and benzodiazepines.

Double Trouble

Prescription records show that as use of opioids like OxyContin and Vicodin soared in the 2000s, so did the use of "benzos" such as Xanax, Klonopin, and Ativan, as opioid users discovered tranquilizers could enhance "the high."

Data provided to the Journal Sentinel and MedPage Today show the drugs are on the upswing again, increasing from 80 million prescriptions in 2006 to 94 million in 2013, according to IMS Health, a drug market research firm.

Now, thousands of Americans are dying each year after mixing opioids and benzodiazepines.

Moore's death was one of 41 accidental overdose fatalities in Milwaukee County in 2012 in which the person had taken both a benzodiazepine and a prescription opioid, according to records supplied by the Medical Examiner's office. That's more than half of 71 accidental overdose deaths involving opioids.

When police used a special factory code to open Moore's safe 3 days after he died, they found hundreds of pills inside, including 82 oxycodone pills and more than 400 benzodiazepines. The Medical Examiner's report said he had taken the opioid oxycodone, three different benzodiazepines, and had been drinking as well.

Moore's injury from the fall required eight surgeries and he suffered chronic pain, according to his mother Jackie Lentz. He also suffered from insomnia and had heart disease. She noted all the medications were prescribed.

"Things just kept getting worse and worse," Lentz said. "He attempted to live a somewhat normal life through the medication."

Repeating Past Mistakes

The U.S. has long loved its tranquilizers, and the recent growth in the use of newer drugs parallels that of old staples like Miltown (meprobamate) in the late 1950s and early 1960s and Librium and Valium in the 1960s and 1970s.

In those cases, the increase was fueled, not by good science, but by drug company marketing -- and now American medicine may be repeating the cycle.

"We are headed in the same direction we did before," said Jerome Wakefield, PhD, a professor of social work and psychiatry at New York University and co-author of "All We Have to Fear: Psychiatry's Transformation of Natural Anxieties into Mental Disorders."

Wakefield said he is especially concerned about primary care practice doctors writing prescriptions for the drugs without having the time to properly monitor patients.

He said Americans increasingly are being put on opioids for pain, hypnotics such as Ambien for sleep disorders, antidepressants, and benzodiazepines.

Over the last few years, several medical journal articles have warned of the heightened danger from co-use of opioids and benzodiazepines:

A 2013 paper in Drug and Alcohol Dependence found that between 2005 and 2009 the combination was the most common cause of overdose deaths involving multiple drugs.

Also in 2013, a paper in Journal of Forensic Sciences found substantial co-use of opioids and benzodiazepines among pregnant or recently pregnant mothers in Florida between 1999 and 2005.

Though benzodiazepines are not intended for long-term use, many pain patients find themselves on opioid/benzodiazepine regimens that last for years, doctors say.

"They are prominent fellow travelers with opioids," said Len Paulozzi, MD, a medical epidemiologist with the CDC. "The problem is, people get on them and they stay on them forever."

How Lethal Is it?

Last month, the state of Ohio turned to an opioid/benzo mix when it could not obtain drugs traditionally used in death row executions. They have been in short supply because European manufacturers have blocked exportation as a protest against capital punishment.

The mixture used to execute Dennis McGuire included midazolam, a benzodiazepine, and hydromorphone, a powerful opioid. The previously untested combination led to a 25-minute, gasping death.

There is little to no evidence demonstrating the efficacy of opioids for chronic pain -- and even less to support the use of opioids plus benzodiazepines, yet as far back as the late 1950s, drug companies ramped up large-scale marketing efforts. The cornerstone of that marketing blitz was a series of advertisements in prominent medical journals directed at doctors -- a campaign that continued through the 1980s.

A Journal Sentinel/MedPage Today review of the ads found they often made questionable claims that tranquilizers were good for ailments including menopause, gastrointestinal problems, ulcers, and cardiovascular symptoms.

In the case of benzodiazepines, institutionalized dispensing of the drugs over the years also is linked to promotional activities of drug companies, a Journal Sentinel/MedPage Today investigation found.

Xanax for the Heart

A 1985 Xanax ad in JAMA claimed the drug relieved cardiovascular symptoms -- a claim for which there was no evidence.

Even today there is no rigorous research indicating that Xanax or other benzodiazepines reduce the risk of heart attacks, strokes, or heart disease, said James Stein, MD, professor of medicine and director of preventive cardiology at the University of Wisconsin School of Medicine and Public Health.

Stein noted that doctors who were in medical school in 1985 may have seen those ads and formed lasting beliefs that benzodiazepines are beneficial for the heart.

"If you learned early in your career, even subliminally, that these drugs were good for the heart or blood vessels, there's an inclination to reach for them," he said.

Pfizer, which sells Xanax, declined to provide a comment on the ad.

Librium for Ulcers

In the 1970s, ads for the benzodiazepine Librium claimed it was beneficial for ulcers.

One such ad in the New England Journal of Medicine said the drug was suitable for extended therapy.

However, a search of the medical literature turned up no rigorous research showing that Librium cured or reduced the severity of ulcers.

"There is no study that shows ulcer healing with anti-anxiolytics (tranquilizers)," said Mitch Roslin, MD, a bariatric surgeon at Lenox Hill Hospital in New York.

He said benzodiazepines were used for ulcers based on the theory that anxious people with type A personalities could benefit by reducing their anxiety.

Tara Iannuccillo, a spokesperson for Roche USA, the manufacturer of the drug, said the company couldn't provide a source to give historical perspective on the marketing of its drugs during that time.

Addiction and Benzos

For years, companies that made tranquilizers said the drugs were safe and nonaddicting.

But in 1975, after widespread reports of abuse, the federal government moved to put Valium, Librium, and some other tranquilizers under the Controlled Substances Act.

By 1978, the U.S. Food and Drug Administration was telling doctors that long-term use of the drugs was unwise because there were no clinical studies indicating the drugs are effective when given over a period of months.

Still, as late as 1980, officials with Hoffman-La Roche argued that their drug Valium was safe and nonaddictive, according to news accounts at the time

They were wrong. The package insert for the drug today clearly states:

"Abuse and dependence of benzodiazepines has been reported. Chronic use (even at therapeutic doses) may lead to the development of physical dependence."

With the 1980 manual, psychiatrists introduced the diagnosis of generalized anxiety disorder.

Revisions to the manual, including an update last year, expanded that diagnosis, which, in turn, meant more people could be treated with tranquilizers, said Allen Frances, MD, the former chair of psychiatry at Duke University. Frances also chaired the panels that developed the 1994 manual.

Among 170 panel members, 56% had financial links to drug companies, according to the paper.

In the field of anxiety disorders, 81% of the panel members had financial connections to drug companies.

For the paper, the researchers included any financial affiliations panel members had with the drug industry between the years of 1989 and 2004.

Separately, benzodiazepines are mentioned favorably in a 2009 national practice guideline for treating panic disorder that also was issued by the American Psychiatric Association.

Five of the seven doctors on that panel, including its chairman, worked as speakers or consultants to drug companies that sold benzodiazepines in the 3 years prior to the publishing of the guideline, according to disclosure statements issued with the document.

This included work for Pfizer, whose drug Xanax XR, won FDA approval for the condition 3 years earlier, according to disclosure statements issued with the guideline.

In an emailed statement, Darrel Regier, a physician and official with the association, said that when the guideline was issued the association required conflicts of interest to be managed by disclosure, extensive reviews of drafts, and oversight by a steering committee that had no members with financial ties to drug companies.

Regier said the diagnostic criteria for anxiety disorders did not change much from the 1980 and 1994 manuals and "would have no appreciable impact on prevalence rates."

He said conflicts of interest standards have toughened since the 1990s. Since 2010, the association only has allowed experts without financial ties to drug companies to serve on its panels, he said.

According to the CDC, 10% of Americans in any given year will be diagnosed with an anxiety disorder, but other estimates put that figure as high as 25%.

Mother's Little Helper

Tranquilizers have long been marketed to women, and data obtained by the Journal Sentinel/MedPage Today indicate the drugs are prescribed twice as often for women.

For example, last year 61 million benzodiazepine prescriptions were written for women, compared with 29 million for men, according to data from IMS Health.

That rate may be a testament to marketing: throughout much of the later half of the 20th century, tranquilizer ads in medical journals urged clinicians to think of their female patients.

The ads portrayed women as needing the drugs to deal with menopause or everyday problems like caring for rowdy children and managing a demanding career.

One ad for a tranquilizer from the late 1950s shows a woman anxiously swatting away a moth, pushing use of the drug for "when she over-reacts to any situation." Another from the 1960s shows a tense mother with several children to represent "the battered parent syndrome."

Ads like those are long gone, but women are still unevenly consuming tranquilizers, said Carolyn Alfieri, who speaks from experience.

Like Mother, Like Daughter

Alfieri is a second-generation prescription drug abuser.

Though she's now been clean 6 years, she waged a long battle with opioid painkillers, and her mother was "hooked on Xanax until the day she died," said Alfieri who lives in California.

Her mother's tranquilizer habit started in the 1960s, when she married young and had two children by age 19.

"My mother started with Miltown and moved to Xanax," Alfieri says. "She was like the stereotypical suburban housewife of the 1960s, reaching for 'mother's little helper,'" a reference to the nickname for Miltown.

Alfieri says that she, too, used benzodiazepines with opioids, mainly as a bridge to hold her over in between opioid doses to diminish symptoms of withdrawal.

Now a resident adviser at a drug-treatment program, Alfieri said benzo use is rampant among the addicted women treated at her center.

"Middle-age women my age are mixing their prescription pain meds with Valium and Xanax," she says. "It's alarming."

For Mary Kate Legacy, her first benzodiazepine prescription came at the age of 11.

The Massachusetts woman, now 20, was first prescribed Ativan for anxiety that was so severe that she could not leave the house to go to school.

Over the years, she was prescribed other benzodiazepines, including Xanax, Valium and Klonopin.

Eventually, Legacy said she began abusing alcohol and narcotic painkillers.

"It (Ativan) was like a gateway for me," she said.

For the last 3 years, Legacy said, she has not used any drugs or alcohol.

She now is an advocate for Heroes in Recovery, a grass roots organization aimed at breaking the stigma of addiction. Heroes was started by the Foundations Recovery Network, which operates treatment centers around the country.

End Game

A 48-year-old Milwaukee woman was not so lucky.

In 2012, she died of an accidental overdose that included the narcotic painkiller oxycodone and alprazolam, the generic version of Xanax, according to the Milwaukee County Medical Examiner's Office.

Because her husband said that he wanted to put her death behind him and not discuss her case, her name is not being used.

She had a history of abusing pain medications to combat back pain after undergoing disc surgery years earlier, the Medical Examiner's report said.

She was one of 18 women to die of an accidental opioid/benzo combination that year in Milwaukee County, according to records.

Medical Examiner records show that in the month prior to her death she got four prescriptions for alprazolam totaling 240 pills.

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